The invention relates to a pharmaceutical composition for the treatment of blood coagulation disorders, especially of Factor VIII inhibitor patients. The invention further relates to a method for production of a composition of this type as well as its use.
Blood coagulation is triggered by a series of successive reactions of various proteins and/or enzymes, The formation of fibrin from fibrinogen and, therewith, the closure of wounds is prevented by a lack of blood coagulation factors; the consequence is hemorrhage. Such a case exists with hemophilia A. This is the most widespread bleeding disorder and is caused by a deficiency in Factor VIII. Factor VIII containing preparations are used for replacement therapy in hemophilia A. Treatment with these preparations leads to a rapid cessation of bleeding in most cases.
However, there are also patients among which not only a deficiency in Factor VIII occurs, but also who have developed an inhibitor directed against Factor VIII. A further collection of patients posses Factor VIII inhibitors without suffering from hemophilia A. Depending on the amount of factor A inhibitors present, the effect of administered Factor VIII is inhibited by its neutralization.
Presently, preparations based on a plasma fraction which contains a mixture of coagulation factors are offered for treatment of Factor VIII inhibitor patients. This plasma fraction can contain, for example, factors of the prothrombin complex (Factor II, VII, IX, X). A blood coagulation promoting preparation with Factor VIII inhibitor bypass activity (FEIBA.RTM. TIM 4, Immuno AG) is obtained, according to AT-0 368 883 (11/82) for example, by treatment of cryosupernatant.
This preparation also contains coagulation Factors II, VII, IX, X.
The action of a FEIBA preparation is complex due to its complex composition. Mariani et al (Thromobosis Res. 31, 475-488, (1983)) mentions Factor VII in its activated form as a principle of action. It was established that a higher content of Factor VIIa in plasma occurs in hemophiliacs after infusion of a FEIBA preparation.
Equally, the role of Factor VIIa in prothrombin complex concentrates with a "Factor VIII-bypassing-activity" is discussed by Teitel (Thrombosis and Haemostasis 66 (5) 559-564, (1991)). Simultaneously, the principle of action of Factor Xa in preparations of this type is also dealt with. The examined prothrombin complex concentrates contained Factor VIIa, expressed by the ratio of Factor VII activity to Factor VII antigen of 2.1 and 2.5.
The therapeutic composition containing prothrombin produced according to EP-0 044 343-B1 (1/82) is suitable for treatment of coagulation factor inhibitors and contains an activated prothrombin complex in which the factors are partially activated. The amount of Factor VIIa is between 8-80 units per ml. Factor IX concentration is in the range of 15 to 112 unfits per ml. Correspondingly, the content of Factor VIIa, with respect to Factor IX, is 0.07-5.3 U Factor VIIa/U Factor IX. Vinazzer (Thromobosis Res. 26:21-29 (1982)) demonstrates the difference of the preparations AUTOPLEX, which is produced according to EP-44 343 (1/82)and FEIBA. As shown there, AUTOPLEX is distinguished by the higher content of thrombin (Factor IIa) measured in NIH units in comparison to FEIBA (see table 1, page 24).
However, highly purified Factor VIIa preparations are also proposed for therapy of coagulation factor inhibitor conditions (for example, EP 0 082 182-B1(6/83) and Hedner et al. (Haemostasis 19, 335-343 (1989)).
A method for the production of a concentrate which contains highly purified Factor VIIa is also described in EP 0 547 932-A1 (6/93). Factor VII is separated from coagulation Factors II, IX and X by anion exchange chromatography of a cryoprecipitate. Factor VII is then subjected to a further purification and activation, whereby the addition of exogenous proteins is avoided. Subsequently, Factor VIIa is treated for inactivation of viruses by a treatment with an organic solvent/detergent (TnBP/Tween.RTM.).
The risk of transmitting infectious agents exists by the use of plasma or a plasma fraction as the starting material for the production of pharmaceutical preparations. Despite selection of donors and tests of the individual plasma donations for possibly present viruses, such as HIV, hepatitis B or hepatitis C virus, the possibility exists that a plasma cool is infectious. This residual infectivity is not to be ruled out because of limited sensitivity of the test systems, but also because of the incubation time until the appearance of measurable infection markers (diagnostic window).
Pharmaceutical preparations which are prepared from plasma or a plasma fraction are therefore subjected to diverse treatments for inactivation of viruses potentially present. A proven method for the inactivation of membrane enveloped as well as non-membrane enveloped viruses is described in EP 0 159 311-B1 (10/85). Thereby, a pharmaceutical preparation is heated in a solid state after adjustment of a water content to a value of 5-70%. This treatment is also described as a steam (vapor) treatment. Instead of water, methanol or ethanol can also be used.
However, combinations of virus inactivation methods are equally possible. According to EP 0 519 901, (12/92) a treatment with highly concentrated tensides is combined with a heat treatment.